Project summary There is an increased incidence of thyroid cancer reported in World Trade Center (WTC) first responders. We found no evidence from our previous research that these are false-positives because of enhanced surveillance of the WTC cohort; it remains unclear why there is this excess risk and in which ways exposure to Ground Zero may be contributing to thyroid malignancy. Moreover, as of yet there has been no research examining the ways in which the thyroid cancers of WTC first responders differ biologically from the non-WTC exposed cohort, especially in terms of the aggressiveness of the tumors. In vitro exposure of rats to WTC dust has been shown to be associated with inflammatory reactions in distant organs. Furthermore, prostate cancer tissue from WTC responders showed a distinct pattern of gene expression, with downregulation of genes involved in innate immunity response and an upregulation of genes related to apoptosis, suggesting that inflammation caused by the inhalation of WTC dust may act as a tumor promoter. Using a 770 gene panel developed by Nanostring, we will characterize the inflammatory and immune microenvironment both in the thyroids of rats directly exposed to WTC dust (aim 1) and tissue from 30 formalin- fixed paraffin-embedded (FFPE) WTC thyroid tumor slides compared to 30 non-WTC exposed cases (aim 2). We will also use whole exome sequencing to look at the genetic alterations driving WTC thyroid cancer development as compared to non WTC exposed cases (aim 3). Specifically we will compare the number of multiple driver mutations as well as mutations validated as more aggressive between the two groups. We will also look for novel driver mutations in the WTC group that may be targets for treatment. This project would represent the first in-depth analysis of the presence of an ?inflammatory microenvironment? in animal thyroid tissue and human thyroid cancer tissue after the inhalation of WTC dust. Linkage of the presence of these markers of inflammation with genetic alterations showing WTC thyroid cancer cases to more aggressive would have implications for the treatment of WTC first responders, justifying an active treatment approach, including surgery, for the WTC thyroid cancer patient population.